1. Field of the Invention
The present disclosure relates generally to pharmaceutical compositions and therapeutic approaches involving compounds that have an anti-cancer effect, particularly through an anti-proliferative mechanism.
2. Description of Related Art
Telomeres are highly specialized structures which are located at the very end of linear chromosomes. Normal human somatic cells progressively lose their telomeres with each cell division primarily due to the end replication problem. While the majority of normal human cells do not have telomerase activity, 85-90% of cancer cells do, which stabilizes their telomeres.
Telomeres are protective structures that are found at the end of linear eukaryotic chromosomes consisting of multiple copies of TTAGGG DNA repeats. Telomeres are associated with six proteins; TRF1, TRF2, TIN2, Rap1, TPP1 and POT1, which all together are called the shelterin complex. (de Lange T., “Shelterin: the protein complex that shapes and safeguards human telomeres,” Genes & Development 2005; 19:2100-10.) The shelterin complex is present at telomeres throughout the cell cycle and have been shown to cap the chromosomal ends from being recognized as DNA damage sites.
Telomeres in all normal somatic cells undergo progressive shortening with each cell division due to the end replication problem, eventually resulting in cellular senescence. However, replication-dependent telomeric shortening can be counteracted by the ribonucleoprotein enzyme, telomerase. Telomerase is a cellular reverse transcriptase that adds TTAGGG repeats to the end of linear chromosomes. Telomerase has two components, hTERT (telomerase catalytic protein component) and hTR or hTERC (telomerase functional or template RNA component). (Greider C W and Blackburn E H, “Telomeres, telomerase and cancer,” Scientific American. 1996; 274:92-7.) While most normal somatic human cells do not have telomerase activity, it is detected, almost universally, in primary human cancer cells (˜85-90%). Thus, the progressive shortening in normal cells without telomerase activity provide an initial barrier for tumorigenesis.
Therefore, in cancer cells telomerase and telomeres represent attractive almost universal targets for therapeutic approaches. Because most normal somatic cells do not have telomerase activity, treatments that selectively target telomerase activity can be beneficial. In addition, treatments that can interfere with telomere sequencing during telomerase activity to interfere with the structure or function of the shelterin complex can also be beneficial.